Pacific salmon populations have declined markedly in the Western United States. Of particular concern is the sublethal neurological injury in salmon exposed to certain pesticides and trace metals. These behavioral impacts include loss of predator detection and prey selection, altered reproductive timing, and loss of homing. The salmon olfactory system is a sensitive target for copper and cadmium-induced peripheral neurotoxicity, and metal-induced oxidative stress may underlie olfactory injury. Neurobehavioral dysfunction similar to that observed for metals has also been demonstrated for anticholinesterase pesticides, and the expression of hepatic biotransformation enzyme isoforms can influence susceptibility to pesticide neurotoxicity. The goal of this new Superfund project is to use molecular, biochemical, and quantitative neurobehaviorial approaches to evaluate the role of hepatic and olfactory biotransformation pathways in susceptibility of coho salmon to neurotoxic injury. We hypothesize that the balance among phase I (e.g. cytochrome P450s, flavin monooxygenases) and phase II (glutathione S-transferase/oxidative defense) pathways is a key determinant of neurotoxic injury in coho salmon, a model salmonid species of ecological relevance to the Pacific Northwest. Our approach will be to initially characterize the high-affinity enzymes responsible for biotransformation of chlorpyrifos and phorate, two organophosphates of particular importance in salmon injury and designated ATSDR Superfund chemicals. GST isoforms that are active in the dealkylation and conjugation of these organophosphates and that protect against oxidative injury will be identified. RNA silencing in coho hepatocytes will be used to evaluate key salmon biotransformation genes that protect against chlorpyrifos injury. The role of oxidative stress in cadmium and copper-induced olfactory injury will be established, and microarray analysis will be used in conjunction with quantitative behavioral studies to functionally link gene expression with metal-induced olfactory injury. Environmental scenarios such as effects of salinity acclimation and co-exposure to metals on chlorpyrifos neurotoxicity will be characterized in vivo, and the effects of residence in a euryhaline Superfund corridor on salmon neurotoxicity will be assessed using robust molecular and biochemical markers developed during the project. It is anticipated that the results of this study will significantly extend our understanding of the role of gene-environment interactions in salmon neurotoxicity.